The invention relates to indol-3-yl derivatives of the formula I 
in which
A and B are each, independently of one another, O, S, NH, NR7, CO, CONH, NHCO or a direct bond,
X is alkylene having 1 to 2 carbon atoms which is unsubstituted or monosubstituted by R4 or R5, or a direct bond,
R1 is H, Z or xe2x80x94(CH2)oxe2x80x94Ar,
R2 is H, R7 or xe2x80x94C(O)Z,
R3 is NHR6, xe2x80x94NR6xe2x80x94C(xe2x95x90NR6)xe2x80x94NHR6, xe2x80x94C(xe2x95x90NR6)xe2x80x94NHR6, xe2x80x94NR6xe2x80x94C(xe2x95x90NR9)xe2x80x94NHR6, xe2x80x94C(xe2x95x90NR9)xe2x80x94NHR6 or Het1,
R4 and R5 are each, independently of one another, H, oxo, R7, xe2x80x94(CH2)oxe2x80x94Ar, xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94Ar, xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94R7, xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94Het, Het, NHR6, NHAr, NHxe2x80x94Het, CONHxe2x80x94R7, CONHxe2x80x94(CH2)oxe2x80x94Ar, CONHxe2x80x94(CH2)oxe2x80x94Het, OR7, OAR, OR6 or Oxe2x80x94Het,
R6 is H, xe2x80x94C(O)R7, xe2x80x94C(O)xe2x80x94Ar, xe2x80x94C(O)xe2x80x94Het, R7, COOR7, COOxe2x80x94(CH2)oxe2x80x94Ar, COOxe2x80x94(CH2)oxe2x80x94Het, SO2xe2x80x94Ar, SO2R7 or SO2xe2x80x94Het,
R7 is alkyl having 1 to 10 carbon atoms or cycloalkyl having 3 to 10 carbon atoms,
R8 is Hal, NO2, CN, Z, xe2x80x94(CH2)oxe2x80x94Ar, COOR1, OR1, CF3, OCF3, SO2R1, NHR1, N(R1)2, NHxe2x80x94C(O)R1, NHCOOR1, COOH, COOZ or C(O)R1,
R9 is CN or NO2,
Z is alkyl having 1 to 6 carbon atoms,
Ar is aryl which is unsubstituted or monosubstituted or polysubstituted by R8,
Hal is F, Cl, Br or l,
Het is a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms may be present and the heterocyclic radical may be monosubstituted or disubstituted by R8,
Het1 is a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical having 5 to 10 ring members and 1 to 4 N atoms which may be unsubstituted or monosubstituted or disubstituted by Hal, R7, OR7, CN, NHZ, oxo or NO2,
n is 0, 1 or 2,
m is 0, 1, 2, 3, 4, 5 or 6, and
o is 0, 1 or 2,
and their physiologically acceptable salts and solvates.
Some similar compounds are disclosed in WO 99/30713 and WO 94/12478.
The object of the invention was to discover novel compounds having valuable properties, in particular those which are used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts are well tolerated and have very valuable pharmacological properties. In particular, they act as integrin inhibitors, inhibiting, in particular, the interactions of the xcex1v-, xcex23- and xcex25-integrin receptors with ligands, such as, for example, the binding of vitronectin to the integrin receptor. Integrins are membrane-bound, heterodimeric glycoproteins consisting of an xcex1 subunit and a smaller xcex2 subunit. The relative affinity and specificity for ligand binding is determined by recombination of the various xcex1 and xcex2 subunits. Particular efficacy is exhibited by the compounds according to the invention in the case of integrins xcex1vxcex21, xcex1vxcex23, xcex1vxcex25, xcex1IIbxcex23, xcex1vxcex26 and xcex1vxcex28, preferably xcex1vxcex23, xcex1vxcex25 and xcex1IIbxcex23. The compounds according to the invention are particularly potent inhibitors of the vitronectin receptor xcex1vxcex23 and/or xcex1vxcex25 and/or of the fibrinogen receptor xcex1IIbxcex23. The compounds according to the invention are particularly preferably inhibitors of the vitronectin receptor xcex1vxcex23.
An essential factor for the activity of integrin inhibitors is the presence of an acid function at a suitable distance from a base centre. The activity and specificity can be controlled by adjusting the spacer length and the type of the base centre. A suitable central template is indole.
xcex1vxcex23 integrin is expressed in a number of cells, for example endothelium cells, cells of smooth vascular muscles, for example the aorta, cells for breaking down bone matrix (osteoclasts) or tumour cells.
The action of the compounds according to the invention can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 1990, 265,12267-12271.
B. Felding-Habermann and D. A. Cheresh in Curr. Opin. Cell. Biol. 1993, 5, 864, describe the significance of the integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially in relation to the vitronectin receptor xcex1vxcex23.
The dependence of formation of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins has been described by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 1994, 264, 569-571.
The possibility of inhibiting this interaction and so initiating apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide has been described by P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Hu, G. Klier and D. A. Cheresh in Cell 1994, 79, 1157-1164. In this, for example, xcex1vxcex23 antagonists or antibodies against xcex1vxcex23 were described which cause shrinkage of tumours due to the initiation of apoptosis.
The experimental evidence that the compounds according to the invention also prevent the attachment of living cells to the corresponding matrix proteins and accordingly also prevent the attachment of tumour cells to matrix proteins can be provided in a cell adhesion test analogously to the method of F. Mitjans et al., J. Cell Science 1995, 108, 2825-2838.
P. C. Brooks in J. Clin. Invest. 1995, 96, 1815-1822, describe xcex1vxcex23 antagonists for combating cancer and for the treatment of tumour-induced angiogenic diseases.
The compounds are able to inhibit the binding of metal proteinases to integrins and thus prevent the cells utilizing the enzymatic activity of the proteinase. An example can be found in the ability of a cyclo-RGD peptide to inhibit the binding of MMP-2 (matrix-metallo-proteinase-2) to the vitronectin receptor xcex1vxcex23, as described in P. C. Brooks et al., Cell 1996, 85, 683-693.
The compounds of the formula I according to the invention can therefore be employed as medicament active ingredients, in particular for the treatment of tumour diseases, osteoporosis, osteolytic diseases and for suppressing angiogenesis.
Compounds of the formula I which block the interaction of integrin receptors and ligands, such as, for example, of fibrinogen to the fibrinogen receptor (glycoprotein IIb/IIIa or xcex1IIxcex23), prevent the spread of tumour cells by metastasis and can therefore be employed as antimetastatic substances in operations in which tumours are removed or attacked surgically. This is confirmed by the following observations:
The spread of tumour cells from a local tumour into the vascular system occurs through the formation of microaggregates (microthromboses) due to the interaction of the tumour cells with blood platelets. The tumour cells are masked by the protection in the microaggregate and are not recognized by the immune system cells. The microaggregates are able to attach to vessel walls, simplifying further penetration of tumour cells into the tissue. Since the formation of microthromboses is promoted by ligand binding to the corresponding integrin receptors, for example xcex1vxcex23 or xcex1IIbxcex23, on activated blood platelets, the corresponding antagonists can be regarded as effective metastasis inhibitors.
Besides the binding of fibrinogen, fibronectin and von Willebrand factor to the fibrinogen receptor of blood platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as victronectin, collagen and laminin, to the corresponding receptors on the surface of various types of cell. In particular, they prevent the formation of blood platelet thromboses and can therefore be employed for the treatment of thromboses, apoplexia, cardiac infarction, inflammations and arteriosclerosis.
The thrombocyte aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature 1962, 4832, 927-929).
The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine, in particular for the prophylaxis and/or therapy of circulation disorders, thromboses, cardiac infarction, arteriosclerosis, apoplexia, angina pectoris, tumour diseases, such as tumour development or tumour metastasis, osteolytic diseases, such as osteoporosis, pathologically angiogenic diseases, such as, for example, inflammations, opthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, restenosis, rheumatic arthritis, osteo-arthritis, rubeotic glaucoma, ulcerative colitis, Crohn""s disease, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing for supporting the healing process.
The compounds of the formula I can be employed as antimicrobial substances in operations where biological materials, implants, catheters or cardiac pacemakers are used. They have an antiseptic action here. The efficacy of the antimicrobial activity can be demonstrated by the method described by P. Valentin-Weigund et al. in Infection and Immunity, 1988, 2851-2855.
A measure of the uptake of a medicament active ingredient in an organism is its bioavailability.
If the medicament active ingredient is administered to the organism intravenously in the form of an injection solution, its absolute bioavailability, i.e. the proportion of the pharmaceutical species which is unchanged in the systemic blood, i.e. enters the general circulation, is 100%. On oral administration of a therapeutic active ingredient, the active ingredient is generally in the form of a solid in the formulation and must therefore first dissolve in order that it can overcome the entry barriers, for example the gastrointestinal tract, the oral mucous membrane, nasal membranes or the skin, in particular the stratum corneum, and can be absorbed by the body. Pharmacokinetic data, i.e. on the bioavailability, can be obtained analogously to the method of J. Shaffer et al., J. Pharm. Sciences, 1999, 88, 313-318.
The invention relates to the compounds of the formula I according to claim 1 and their physiologically acceptable salts and/or solvates as therapeutic active ingredients.
The invention accordingly relates to compounds of the formula I according to claim 1 and their physiologically acceptable salts and/or solvates as xcex1v-integrin inhibitors.
The invention furthermore relates to compounds of the formula I according to claim 1 and their physiologically acceptable salts and/or solvates as GPIIb/IIIa antagonists.
The invention relates to compounds of the formula I according to claim 1 and their physiologically acceptable salts and/or solvates for use in combating diseases.
The compounds of the formula I have at least one centre of chirality and can therefore occur in a number of stereoisomeric forms. All of these forms (for example D and L forms) and their mixtures (for example the DL forms) are included in the formula.
The compounds according to the invention according to claim 1 also cover so-called prodrug derivatives, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the organism to give the effective compounds according to the invention.
Furthermore, free amino groups or free hydroxyl groups can be provided as substituents of compounds of the formula I with corresponding protecting groups.
The term solvates of the compounds of the formula I is taken to mean adductions of inert solvent molecules onto the compounds of the formula I which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or addition compounds with alcohols, such as, for example, with methanol or ethanol.
The invention relates to the compounds of the formula I and their salts and solvates according to claim 1 and to a process for the preparation of compounds of the formula I and their salts and solvates, characterized in that
a) a compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or
b) a radical R1, R2, R3, R4, R5 and/or R6 is converted into another radical R1, R2, R3, R4, R5 and/or R6 for example by
i) converting an amino group into a guanidino group by reaction with an amidating agent,
ii) saponifying an ester,
iii) alkylating or acylating an amino group,
iv) converting a cyano group into an amidino group,
and/or a base or acid of the formula I is converted into one of its salts.
In the formulae above, Z is alkyl, which is linear or branched and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6, carbon atoms. Z is preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. Z is particularly preferably methyl or ethyl.
Alkyl having 1 to 10 carbon atoms may be linear or branched and preferably has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Alkyl having 1 to 10 carbon atoms is preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore also n-pentyl, 1-, 2- or 3-methylbutyl, n-hexyl, 1-, 2-, 3- or 4-methylpentyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
Alkylene having 1 to 2 carbon atoms is methylene or ethylene, where at least one Cxe2x80x94H bond of the alkylene may be replaced by a Cxe2x80x94R4 or Cxe2x80x94R5 bond.
Ar is aryl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R8, where aryl is phenyl, naphthyl, anthryl or biphenyl. Ar is preferably phenyl, naphthyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R8. Ar is particularly preferably phenyl or biphenyl-4-yl, each of which is unsubstituted or monosubstituted or polysubstituted by R8.
Ar is therefore preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p-trifluoromethylphenyl, o-, m-, p-trifluoromethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-carboxyphenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-fluoro-2-hydroxyphenyl, 2,4,6-trifluorophenyl, 2-chloro-3,6-difluorophenyl, 3-cyano-4-dimethylamino-2-fluorophenyl or biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethylnaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-fluoronaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-bromonaphthalen-1-yl, 2-, 3-, 4-, 5, 6-, 7- or 8-hydroxynaphthalen-1-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-ethylnaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7, or 8-chloronaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-fluoronaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-bromonaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7 or 8-hydroxynaphthalen-2-yl.
Ar is particularly preferably phenyl, m- or p-trifluoromethoxyphenyl, p-isopropylphenyl, p-fluorophenyl, m-chlorophenyl, m-hydroxyphenyl, p-carboxyphenyl, 2,4- or 3,5-dichlorophenyl, 4-chloro-3-trifluoromethylphenyl, 2,6-, 3,4- or 3,5-difluorophenyl, 3-fluoro-4-trifluoromethylphenyl, 2,4,6-trifluorophenyl, 2-chloro-3,6-difluorophenyl, 3-cyano-4-dimethylamino-2-fluorophenyl or biphenyl-4-yl. Ar is very particularly preferably p-fluorophenyl.
C(O)Z is alkanoyl and is preferably formyl, acetyl, propionyl, butyryl, pentanoyl or hexanoyl.
C(O)xe2x80x94Ar is aroyl, where Ar is as defined above. Particular preference is given to benzoyl.
COOxe2x80x94(CH2)oxe2x80x94Ar is arylalkyloxycarbonyl, where xe2x80x94(CH2)oxe2x80x94Ar is as defined below. Particular preference is given to benzyloxycarbonyl.
Cycloalkyl having 3 to 10 carbon atoms is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Cycloalkyl is likewise a monocyclic or bicyclic terpene, preferably p-menthane, menthol, pinane, bornane or camphor, where each known stereoisomeric form is included, or adamantyl. For camphor, this is both L-camphor and D-camphor.
xe2x80x94(CH2)oxe2x80x94Ar is preferably Ar for o=0 or benzyl, phenylethyl or naphthylmethyl for o=1 or 2. xe2x80x94(CH2)oxe2x80x94Ar is particularly preferably benzyl for o=1 or Ar for o=0.
Hal is F, Cl, Br or 1, particularly preferably F, Cl or Br.
Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -4 or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7- benzofuryl, 2-3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1H-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 4- or 5-benzothiadiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals may also be partially or fully hydrogenated. Het can thus also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6- or -7-1H-indolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl.
Het is preferably Z-substituted or unsubstituted morpholin-4-yl, tetrahydropyran-4-yl, piperidin-4-yl, indol-2-yl, pyrrol-2-yl, pyridin-4-yl, thiophen-2-yl, thiazol-2-yl or benzothiadiazol-5-yl. Het is particularly preferably unsubstituted indol-2-yl, pyrrol-2-yl, pyridin-4-yl, thiophen-2-yl, thiazol-2-yl or benzothiadiazol-5-yl.
Het1 is preferably substituted or unsubstituted 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1H-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals may also be partially or fully hydrogenated. Het1 can thus also be 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1H-indolyl, 2,3-dihydro-1-, -2-, -3, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,5-dihydroimidazol-4-on-2- or -5-yl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, tetrahydro-2-, -3- or -4-pyranyl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl.
The said heterocyclic rings may also be monosubstituted or disubstituted by xe2x95x90O or NHZ.
Het1 is particularly preferably 3-nitropyridin-2-yl, 3-aminopyridin-2-yl, 3-(N-acetylamino)pyridin-2-yl, pyridin-2-yl, 1,4,5,6-tetrahydropyridin-2-yl, benzimidazol-2-yl, imidazol-2-yl, 4,5-dihydroimidazol-2-yl, 3,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl.
A and B are each, independently of one another, O, S, NH, NR7, CO, CONH, NHCO or a direct bond, where R7 is as defined below. A is particularly preferably NH, CONH, NHCO or a direct bond, very particularly preferably NH. B is particularly preferably O or a direct bond, very particularly preferably O.
X is alkylene having 1 to 2 carbon atoms which is unsubstituted or mono-substituted by R4 or R5, where R4 and R5 are as defined below, or a direct bond. X is particularly preferably a bond or phenyl-substituted methylene. X is very particularly preferably a direct bond.
m is 0, 1, 2, 3, 4, 5 or 6. m is particularly preferably 3 or 4. m is very particularly preferably 3.
n is 0, 1 or 2. n is particularly preferably 0.
o is 0, 1 or 2, preferably 0 or 1, particularly preferably 0
R1 is H, Z or xe2x80x94(CH2)0xe2x80x94Ar, where Z, o and xe2x80x94(CH2)oxe2x80x94Ar are as defined above.
R1 is particularly preferably H.
R2 is H, R7 or xe2x80x94C(O)Z, where R7 is as defined below, and Z is as defined above. R2 is particularly preferably H, methyl or acetyl. R2 is very particularly preferably H.
R3 is NHR6, xe2x80x94NR6xe2x80x94C(xe2x95x90NR6)xe2x80x94NHR6, xe2x80x94C(xe2x95x90NR6)xe2x80x94NHR6, xe2x80x94NR6xe2x80x94C(xe2x95x90NR9)xe2x80x94NHR6, xe2x80x94C(xe2x95x90NR9)xe2x80x94NHR6 or Het1, where R6 is as defined below and Het1 is as defined above. R3 is preferably amino, guanidino, NHBoc, xe2x80x94C(xe2x95x90N-Boc)-NHBoc, xe2x80x94NHxe2x80x94C(xe2x95x90N-Boc)-NHBoc, NBoc-C(xe2x95x90N-Boc)-NH2, where Boc is tert-butoxycarbonyl, xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94CN)xe2x80x94NR6 or xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94NO2)xe2x80x94NR6, where R6 is as defined below, or 3-nitropyridin-2-yl, 3-aminopyridin-2-yl, 3-(N-acetylamino)pyridin-2-yl, pyridin-2-yl, 1,4,5,6-tetrahydropyridin-2-yl, benzimidazol-2-yl, imidazol-2-yl, 4,5-dihydroimidazol-2-yl, 3,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl. R3 is particularly preferably 1H-imidazol-2-yl, 4,5-dihydroimidazol-2-yl, 3,5-dihydroimidazol-4-on-2-yl or pyridin-2-yl.
R4 and R5 are each, independently of one another, H, oxo, R7, xe2x80x94(CH2)oxe2x80x94Ar, xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94Ar, xe2x80x94C(O)xe2x80x94(CH2)oR7, xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94Het, Het, NHR6, NHAr, NHxe2x80x94Het, CONHxe2x80x94R7, CONHxe2x80x94(CH2)oxe2x80x94Ar, CONHxe2x80x94(CH2)oxe2x80x94Het, OR7, OAr, OR6 or Oxe2x80x94Het, where Ar and Het are as defined above, and R6 and R7 are as defined below.
xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94Ar is preferably phenylcarbonyl, benzylcarbonyl or phenylethylcarbonyl.
In xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94R7, R7 is as defined below. xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94R7 is preferably acetyl, propionyl, butanoyl, cyclohexylcarbonyl, cyclopentylcarbonyl, cyclohexylmethylcarbonyl or cyclohexylethylcarbonyl.
In xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94Het, Het is as defined above. xe2x80x94C(O)xe2x80x94(CH2)oxe2x80x94Het is preferably pyridin-4-ylcarbonyl, pyridin-4-ylmethylcarbonyl or pyridin-4-yl-ethylcarbonyl.
In CONHxe2x80x94R7, R7 is as defined below. xe2x80x94CONHxe2x80x94R7 is preferably methylaminocarbonyl, ethylaminocarbonyl, cyclohexylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylmethylaminocarbonyl or cyclohexylethylaminocarbonyl. CONHxe2x80x94(CH2)oxe2x80x94Ar is preferably phenylaminocarbonyl, benzylaminocarbonyl or phenylethylaminocarbonyl.
CONHxe2x80x94(CH2)oxe2x80x94Het is preferably pyridin-4-ylaminocarbonyl, pyridin-4-yl-methylaminocarbonyl or pyridin-4-ylethylaminocarbonyl.
R4 and R5 are preferably each, independently of one another, H, xe2x80x94(CH2)oxe2x80x94Ar, R7 or Het, where o is 0 or 1. R4 is particularly preferably phenyl, 3-trifluoromethoxyphenyl, 4-fluorophenyl, 3-chlorophenyl, 3-hydroxyphenyl, pyridin-4-yl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, cyclohexyl, 4-chloro-3-trifluoromethylphenyl, benzothiadiazol-4-yl, 2,6-difluorophenyl, 2-chloro-3,6-difluorophenyl, 2,4,6-trifluorophenyl or cyclohexyl. R5 is particularly preferably H.
R6 is preferably H, xe2x80x94C(O)R7, xe2x80x94C(O)xe2x80x94Ar, R7, COOR7, COOxe2x80x94(CH2)oxe2x80x94Ar, SO2xe2x80x94Ar, SO2R7 or SO2xe2x80x94Het, where Ar and Het are as defined above, and R7 is alkyl having 1 to 10 carbon atoms or cycloalkyl having 3 to 10 carbon atoms. R6 is preferably H, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl.
R7 is alkyl having 1 to 10 carbon atoms or cycloalkyl having 3 to 10 carbon atoms, where the terms alkyl and cycloalkyl are as defined above. R7 is preferably tert-butyl, 2,2-dimethylpropyl, cyclopropyl or cyclohexyl.
R8 is Hal, NO2, CN, Z, xe2x80x94(CH2)oxe2x80x94Ar, COOR1, OR1, CF3, OCF3, SO2R1, NHR1, N(R1)2, NHxe2x80x94C(O)R1, NHCOOR1 or C(O)R1, where Hal, Z, xe2x80x94(CH2)oxe2x80x94Ar and R1 are as defined above.
R9 is CN or NO2, particularly preferably CN.
Preferred versions of the substituent R3xe2x80x94(CH2)nxe2x80x94Axe2x80x94(CH2)mxe2x80x94Bxe2x80x94 are 
The substituent R3xe2x80x94(CH2)nxe2x80x94Axe2x80x94(CH2)mxe2x80x94Bxe2x80x94 is preferably in the 5- or 6-position of the indole ring, particularly preferably in the 6-position.
Accordingly, the invention relates in particular to compounds of the formula I in which at least one of said radicals has one of the preferred meanings given above. Some preferred groups of compounds may be expressed by the following sub-formulae Ia to Ii, which correspond to the formula I and in which radicals not denoted in greater detail are as defined in the formula I, but in which
In Ia X is a direct bond 
In Ib X is a direct bond,
R2 is H,
R5 is H,
R4 is (CH2)oxe2x80x94Ar, and
o is 0 
In Ic X is a direct bond,
R5 is H,
R4 is (CH2)oxe2x80x94Ar or Het, and
o is 0;
In Id X is a direct bond,
R5 is H,
B is O,
A is NH,
n is 0,
m is 3 or 4,
R3 is Het1,
R4 is (CH2)oxe2x80x94Ar, and
o is 0
In Ie X is a direct bond,
R5 is H,
B is O,
A is NH,
n is 0,
m is 3 or 4, and
R3 is Het1
In If X is methylene which is unsubstituted or substituted by Ar,
R2 is H,
R5 is H or Ar, and
R4 is oxo 
In Ig X is methylene, 
In Ih X is methylene,
R4 is H or (CH2)oxe2x80x94Ar,
R5 is H or (CH2)oxe2x80x94Ar,
o is 0, and
R2 is H;
In Ii X is methylene,
R4 is H or (CH2)oxe2x80x94Ar,
R5 is H or (CH2)oxe2x80x94Ar,
o is 0,
B is O,
A is NH,
n is 0,
m is 3 or 4,
R3 is Het1, and
R2 is H 
The compounds of the formula I according to claim 1 and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I according to claim 1.
Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent.
Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, in particular those which instead of an Hxe2x80x94N group carry an SG1xe2x80x94N group, in which SG1 is an amino protecting group, and/or those which instead of an H atom of a hydroxyl group carry a hydroxyl protecting group, for example those which conform to the formula I, but instead of a xe2x80x94COOH group carry a xe2x80x94COOSG2 group, in which SG2 is a hydroxyl protecting group.
It is also possible for a plurality of identical or different protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be removed selectively (cf. in this respect: T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, 2nd Edn., Wiley, New York 1991, or P. J. Kocienski, Protecting Groups, 1st Edn., Georg Thieme Verlag, Stuttgart-New York, 1994, H. Kunz, H. Waldmann in Comprehensive Organic Synthesis, Vol. 6 (Eds. B. M. Trost, I. Fleming, E. Winterfeldt), Pergamon, Oxford, 1991, pp. 631-701).
The term xe2x80x9camino protecting groupxe2x80x9d is generally known and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or synthesis sequence), their type and size is furthermore not crucial; however, preference is given to those having 1-20 carbon atoms. The term xe2x80x9cacyl groupxe2x80x9d is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived aliphatic, araliphatic, alicyclic, aromatic and heterocyclic carboxylic acids and from sulfonic acids, as well as, in particular, alkoxycarbonyl, alkenyloxycarbonyl, aryloxy-carbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc and 2-iodoethoxycarbonyl; alkenyloxycarbonyl, such as allyloxycarbonyl (Aloc), aralkoxycarbonyl, such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (Fmoc); 2-(phenylsulfonyl)ethoxycarbonyl; trimethylsilylethoxycarbonyl (Teoc), and arylsulfonyl, such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino protecting groups are Boc, Fmoc and Aloc, furthermore Z, benzyl and acetyl.
The term xe2x80x9chydroxyl protecting groupxe2x80x9d is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, furthermore also alkyl groups, alkyl-, aryl- and aralkylsilyl groups, and O, O- and O,S-acetals. The nature and size of the hydroxyl protecting groups is not crucial since they are removed again after the desired chemical reaction or synthesis sequence; preference is given to groups having 1-20 carbon atoms, in particular 1-10 carbon atoms. Examples of hydroxyl protecting groups are, inter alia, aralkyl groups, such as benzyl, 4-methoxybenzyl and 2,4-dimethoxybenzyl, aroyl groups, such as benzoyl and p-nitrobenzoyl, acyl groups, such as acetyl and pivaloyl, p-toluenesulfonyl, alkyl groups, such as methyl and tert-butyl, but also allyl, alkylsilyl groups, such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and triethylsilyl, trimethylsilylethyl, aralkylsilyl groups, such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals, such as isopropylidene acetal, cyclopentylidene acetal, cyclohexylidene acetal, benzylidene acetal, p-methoxybenzylidene acetal and o,p-dimethoxybenzylidene acetal, acyclic acetals, such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) and methylthiomethyl (MTM). Particularly preferred hydroxyl protecting groups are benzyl, acetyl, tert-butyl and TBS.
The liberation of the compounds of the formula I from their functional derivatives is known from the literature for the protecting group used in each case (for example T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, 2nd Edn., Wiley, New York 1991 or P.J. Kocienski, Protecting Groups, 1st Edn., Georg Thieme Verlag, Stuttgart-New York, 1994). Use may also be made here of variants which are known per se, but are not mentioned here in greater detail.
Compounds of the formula I in which R3=Het1, B=O, A=NH and n=0 (formula I-1) can preferably be obtained in accordance with reaction scheme 1 below. SG3 and SG4 are hydroxyl protecting groups as defined above. SG5 is an amino protecting group as described above. The radicals X, R1, R2, R4 and R5 and the variable m mentioned in the compounds I-1 and II-VI are as defined in claim 1. 
After removal of the hydroxyl protecting group SG4 from the compound of the formula II under the corresponding known reaction conditions, a reaction is carried out with the compound of the formula III analogously to reaction conditions of nucleophilic substitutions. Under the known reaction conditions for a Mitsunobu reaction [literature: O. Mitsunobu, Synthesis 1981, 1-28], a reaction with a compound of the formula V is carried out in the subsequent step, and the amino protecting group SG5 is correspondingly deblocked. Removal of the hydroxyl protecting group SG3 gives a free acid of the formula I-1 (R1=H). If desired, the hydroxyl protecting group SG3 is converted into a substituent R1.
The invention likewise relates to compounds of the formula IIa 
in which R2, R4 and R5 are as defined in claim 1,
X is a bond,
R10 is a hydroxyl protecting group or H, and
R11 is a hydroxyl protecting group or H.
R10 is preferably H or an alkyl group Z as hydroxyl protecting group, where
Z is as defined above.
R11 is preferably H or an aralkyl group as hydroxyl protecting group, as described above. The hydroxyl group OR11 is preferably in the 6-position of the indole ring. Compounds of the formula IIa are valuable intermediates in the synthesis of the compounds of the formula I according to the invention in which X is a bond.
Preferred compounds of the formula IIa are
ethyl 3-phenyl-3-(6-O-benzyl-indol-3-yl)propionate;
ethyl 3-phenyl-3-(6-hydroxy-indol-3-yl)propionate;
ethyl 3-phenyl-3-(5-O-benzyl-indol-3-yl)propionate;
ethyl 3-phenyl-3-(5-hydroxy-indol-3-yl)propionate;
ethyl 3-(4-methylphenyl)-3-(6-O-benzyl-indol-3-yl)propionate;
ethyl 3-(4-methylphenyl)-3-(6-hydroxy-indol-3-yl)propionate;
ethyl 3-(3-methylphenyl)-3-(6-O-benzyl-indol-3-yl)propionate;
ethyl 3-(3-methylphenyl)-3-(6-hydroxy-indol-3-yl)propionate;
ethyl 3-(2-methylphenyl)-3-(6-O-benzyl-indol-3-yl)propionate;
ethyl 3-(2-methylphenyl)-3-(6-hydroxy-indol-3-yl)propionate;
ethyl 3-[(4-trifluoromethyl)phenyl]-3-(6-O-benzylindol-3-yl)propionate;
ethyl 3-[(4-trifluoromethyl)phenyl]-3-(6-hydroxyindol-3-yl)propionate;
ethyl 3-(4-methoxyphenyl)-3-(6-O-benzylindol-3-yl)propionate;
ethyl 3-(4-methoxyphenyl)-3-(6-hydroxyindol-3-yl)propionate;
ethyl 3-(4-ethoxyphenyl)-3-(6-O-benzylindol-3-yl)propionate;
ethyl 3-(4-ethoxyphenyl)-3-(6-hydroxyindol-3-yl)propionate;
ethyl 3-(4-chlorophenyl)-3-(6-O-benzylindol-3-yl)propionate;
ethyl 3-(4-chlorophenyl)-3-(6-hydroxyindol-3-yl)propionate;
ethyl 3-(3-chlorophenyl)-3-(6-O-benzylindol-3-yl)propionate;
ethyl 3-(3-chlorophenyl)-3-(6-hydroxyindol-3-yl)propionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-pyridin-4-ylpropionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-pyridin-4-ylpropionate;
ethyl 3-benzo-1,2,5-thiadiazol-4-yl-3-(6-benzyloxy-1H-indol-3-yl)propionate;
ethyl 3-benzo-1,2,5-thiadiazol-4-yl-3-(6-hydroxy-1H-indol-3-yl)propionate;
ethyl 3-benzo-1,2,5-thiadiazol-5-yl-3-(6-benzyloxy-1H-indol-3-yl)propionate;
ethyl 3-benzo-1,2,5-thiadiazol-5-yl-3-(6-hydroxy-1H-indol-3-yl)propionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-naphthalen-1-ylpropionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-naphthalen-1-ylpropionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-naphthalen-2-ylpropionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-naphthalen-2-ylpropionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(thiophen-2-yl)propionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(thiophen-2-yl)propionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(1H-pyrrol-2-yl)propionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(1H-pyrrol-2-yl)propionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(thiazol-2-yl)propionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(thiazol-2-yl)propionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-3-(1H-indol-2-yl)propionate;
ethyl 3-biphenyl-4-yl-3-(6-benzyloxy-1H-indol-3-yl)propionate;
ethyl 3-biphenyl-4-yl-3-(6-hydroxy-1H-indol-3-yl)propionate;
ethyl 3-(3-cyano-4-dimethylamino-2-fluorophenyl)-3-(6-benzyloxy-1H-indol-3-yl)propionate;
ethyl 3-(3-cyano-4-dimethylamino-2-fluorophenyl)-3-(6-hydroxy-1H-indol-3-yl)propionate;
ethyl 3-(3-fluoro-4-trifluoromethylphenyl)-3-(6-benzyloxy-1H-indol-3-yl)-propionoate;
ethyl 3-(3-fluoro-4-trifluoromethylphenyl)-3-(6-hydroxy-1H-indol-3-yl)-propionate;
ethyl 3-(4-isopropylphenyl)-3-(6-benzyloxy-1H-indol-3-yl)propionate;
ethyl 3-(4-isopropylphenyl)-3-(6-hydroxy-1H-indol-3-yl)propionate;
ethyl 3-cyclohexyl-3-(6-benzyloxy-1H-indol-3-yl)propionate;
ethyl 3-cyclohexyl-3-(6-hydroxy-1H-indol-3-yl)propionate;
ethyl 3-cyclopropyl-3-(6-benzyloxy-1H-indol-3-yl)propionate;
ethyl 3-cyclopropyl-3-(6-hydroxy-1H-indol-3-yl)propionate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-4,4-dimethyl-pentanoate;
ethyl 3-(6-hydroxy-1H-indol-3-yl)-4,4-dimethyl-pentanoate;
ethyl 3-(6-benzyloxy-1H-indol-3-yl)-5,5-dimethyl-hexanoate or
ethyl 3-(6-hydroxy-1H-indol-3-yl)-5,5-dimethyl-hexanoate.
Compounds of the formula IIa, as defined above, can be prepared analogously to Example 1 in accordance with reaction scheme 1a, where R5 is H and R11 is a hydroxyl protecting group SG4. 
The condensation of a compound of the formula (1a-I) with an aldehyde XI and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum""s acid) under reaction conditions known for condensation reactions gives compounds of the formula (1a-II). Combined ester cleavage/decarboxylation/esterification gives the ethyl ester of the formula (1a-III). The hydroxyl protecting group SG4 can be removed by methods known from the literature, giving the free hydroxyl compounds of the formula IIa. Ester cleavage of the compounds of the formula (1a-II) or the hydroxyl analogues en gives the free acids of the formula IIa.
Compounds of the formula I in which R3=Het1, B=O, A=NHCO and n=0 (Formula I-2) can preferably be obtained in accordance with reaction scheme 2 below. SG3, SG4 and SG6 are hydroxyl-protecting groups as defined above. The radicals X, R1, R2, R4 and R5 and the variable m mentioned in the compounds I-2, II and VII to IX are as defined in claim 1. 
After removal of the hydroxyl protecting group SG4 from the compound of the formula II under the corresponding known reaction conditions, a reaction is carried out with the compound of the formula VII analogously to reaction conditions of nucleophilic substitutions. After removal of the hydroxyl protecting group SG6, a reaction with a compound of the formula IX is carried out under the known reaction conditions for peptide-analogous couplings. Removal of the hydroxyl protecting group SG3 gives a free acid of the formula I-2 (R1=H). If desired, the hydroxyl protecting group SG3 is converted into a substituent R1.
Compounds of the formula I in which B=O, X=a bond, R1=H and R5=H (formula I-3) can preferably be obtained in accordance with reaction scheme 3 below. The radicals R3, R2 and R4 and the variables A, n and m mentioned in the compounds X-XII are as defined in claim 1, where free amino groups in R3 are protected by amino protecting groups during the synthesis, and the protecting groups are removed in the final reaction step. 
The condensation of a compound of the formula X with an aldehyde XI and 2,2-dimethyl-1,3-dioxane-4,6-dione under reaction conditions which are known for condensation reactions gives compounds of the formula XII. Ester cleavage and decarboxylation give the free acid of the formula I-3. If desired, the hydroxyl group is converted into a substituent R1 or the acid of the formula I-3 is converted into a physiologically acceptable salt. Compounds of the formula X are obtained by alkylation of 1H-indol-6-ol using a bromide of the formula XIII (R3xe2x80x94(CH2)nxe2x80x94Axe2x80x94(CH2)mxe2x80x94Br XIII), in which said radical R3 and the variables A, n and m are as defined in claim 1.
Compounds of the formula I in which R3=Het1, R5=H, X=a bond, A=NH, B=O and n=0 (formula I-4) can preferably be obtained in accordance with reaction scheme 4 below. In the compounds of the formula Iia, as described above, R10 is SG3 and R11 is SG4 (formula Iia-1), where SG3 and SG4 are hydroxyl protecting groups, as defined above. SG5 is an amino protecting group as described above. The radicals R1, R2 and R4 and the variable m mentioned in the compounds I-4 and XV-XVIII are as defined in claim 1. 
After removal of the hydroxyl protecting group SG4 from the compound of the formula Iia-1 in reaction scheme 4 under the corresponding known reaction conditions, a reaction is carried out with the compound of the formula XV analogously to reaction conditions of nucleophilic substitutions. In the subsequent step, the amino protecting group SG5 is removed, and the free amine is reacted with a thiomethyl or chloro compound of the formula XVII. Removal of the hydroxyl protecting group SG3 gives a free acid of the formula I-4 (R1=H). If desired, the hydroxyl protecting group SG3 is converted into a substituent R1.
Compounds of the formula I in which R3=xe2x80x94C(xe2x95x90NR6)xe2x80x94NHR6 or xe2x80x94C(xe2x95x90NR9)xe2x80x94NHR6, R5=H, X=a bond, A=NH, B=O and n=0 (formula I-5) can likewise preferably be obtained in accordance with reaction scheme 4. 
Instead of the reaction with compounds of the formula XVII (Het1-SMe or Het1-Cl), however, a reaction is carried out with a compound of the formula XIX 
or a compound of the formula XX
Mexe2x80x94Sxe2x80x94C(xe2x95x90NR6/9)xe2x80x94SMexe2x80x83xe2x80x83XX
with subsequent substitution by an amine of the formula XXI
R6NH2xe2x80x83xe2x80x83XXI.
The radicals R6 and R9 mentioned in the compounds I-4 and XIX-XXI are as defined in claim 1.
Compounds of the formula X 
in which R2, R3, A, n and m are as defined in claim 1, can be prepared analogously to the synthesis sequence in reaction scheme 4 by replacing the compound IIa-1 with a hydroxyl-substituted indole compound XXII 
in which R2 is as defined in claim 1. After reaction of the hydroxyindole XXII with a compound of the formula XV and removal of the amino protecting group SG5, as described above, reaction is possible, depending on the substituent R3, with a compound of the formula XVII or XIX or with a compound of the formula XX followed by reaction with a compound of the formula XXI. Free amino groups in compounds of the formula XVII are protected by amino protecting groups during the synthesis.
The invention likewise relates to compounds of the formula X 
in which
R2, R3, A, n and m are as defined in claim 1, or salts thereof.
Preferred compounds of the formula X are
6-(3-(N-benzylpyridinium-2-yl-amino)propoxy)indole;
6-(3-(N-benzylpyridinium-2-yl-amino)propoxy)indole hydrobromide;
6-(3-(pyridin-2-yl-amino)propoxy)indole;
6-[3-(4,5-dihydro-1H-imidazol-2-yl-amino)propoxy]indole or
6-[3-(4,5-dihydro-1H-imidazol-2-yl-amino)butoxy]indole.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene and xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform and dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol and tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) and dioxane; glycol ethers, such as ethylene glycol monomethyl and monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone and butanone; amides, such as acetamide, dimethylacetamide and dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid and acetic acid; nitro compounds, such as nitromethane and nitrobenzene; esters, such as ethyl acetate, and mixtures of said solvents.
It is furthermore possible for a radical R1, R2, R3, R4, R5 and/or R6 to be converted into another radical R1, R2, R3, R4, R5 and/or R6.
It is thus possible to saponify an ester of the formula I under standard conditions, for example NaOH in dioxane/water, 0-60xc2x0 C.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine followed by reduction of the N-hydroxyamidine using hydrogen in the presence of a catalyst, such as, for example, Pd/C.
In order to prepare an amidine of the formula I (R3=xe2x80x94C(xe2x95x90NH)xe2x80x94NH2), ammonia can be adducted onto a nitrile of the formula I. The adduction is preferably carried out in a number of steps by, in a manner known per se, a) converting the nitrile into a thioamide using H2S and then converting the thioamide into the corresponding S-alkylimidothioester using an alkylating agent, for example CH3l, and then reacting the thioester with NH3 to give the amidine, b) converting the nitrile into the corresponding imido ester using an alcohol, for example ethanol in the presence of HCl, and treating this ester with ammonia, or c) reacting the nitrile with lithium bis(trimethylsilyl)amide, and subsequently hydrolysing the product.
The conversion of an amino group into a guanidino group is carried out using an amidating agent, for example 1-amidino-3,5-dimethylpyrazole (DPFN), which is employed, in particular, in the form of its nitrate. The conversion is advantageously carried out with addition of a base, such as triethylamine or ethyl diisopropylamine, in an inert solvent or solvent mixture, for example water/dioxane, at temperatures of from 0 to 120xc2x0 C., preferably from 60 to 120xc2x0 C.
Furthermore, free amino groups can be acylated in a conventional manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures of from xe2x88x9260 to +30xc2x0 C.
A base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as, for example, orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and -disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I. On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Suitable salts are furthermore substituted ammonium salts, for example the dimethyl-, diethyl- and diisopropylammonium salts, monoethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
The compounds of the formula I contain at least one centre of chirality and can therefore exist in racemic or optically active form. Racemates obtained can be resolved into the isomers mechanically or chemically by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids, such as xcex2-camphorsulfonic acid. Also advantageous is enantiomer resolution with the aid of a column filled with an optically active resolving agent (for example dinitrobenzoylphenylglycine); an example of a suitable eluent is a hexane/isopropanol/acetonitrile mixture, for example in the volume ratio 82:15:3.
The diastereomer resolution can also be carried out by standard purification processes, such as, for example, chromatography or fractional crystallization.
It is of course also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
The invention furthermore relates to pharmaceutical preparations comprising at least one compound of the formula I and/or a physiologically acceptable salt or solvate thereof prepared, in particular, by non-chemical methods. The compounds of the formula I can be brought into a suitable dosage form here together with at least one solid, liquid and/or semiliquid excipient or assistant and, if desired, in combination with one or more further active ingredients.
These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds can also be lyophilized and the resultant lyophilizates used, for example, for the preparation of injection preparations. The preparations indicated may be sterilized and/or comprise assistants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
For administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO2 or chlorofluorocarbons). The active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol. Inhalation solutions can be administered with the aid of conventional inhalers.
The compounds of the formula I and their physiologically acceptable salts can be used as integrin inhibitors in the combating of illnesses, in particular thromboses, cardiac infarction, coronary heart diseases, arteriosclerosis, tumours, osteoporosis, inflammations and infections.
The compounds of the formula I according to claim 1 and/or their physiologically acceptable salts are also used in pathological processes which are maintained or propagated by angiogenesis, in particular in tumours, restenoses, diabetic retinopathy, macular degenerative disease or rheumatoid arthritis.
The substances according to the invention are generally administered analogously to other known commercially available peptides, but in particular analogously to the compounds described in WO 99/30713 and WO 94/12478, preferably in doses of from about 0.05 to 500 mg, in particular from 0.5 to 100 mg, per dosage unit. The daily dose is preferably from about 0.01 to 2 mg/kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the rate of excretion, medicament combination and severity of the particular illness to which the therapy applies. Parenteral administration is preferred.
Above and below, all temperatures are given in xc2x0 C. In the examples below, xe2x80x9cconventional work-upxe2x80x9d means that the organic phase is washed with saturated NaHCO3 solution, if desired with water and saturated NaCl solution, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel, by preparative HPLC and/or by crystallization. If desired, the purified compounds are freeze-dried.
HPLC: eluent A=water+0.3% of TFA, eluent B=acetonitrile/water+0.3% of TFA in the ratio 4:1. Rt denotes the retention time. Rf denotes the retention factor.